A new recessive, lethal mutation (nku) with severe effects on lung development in the mouse is under study. Homozygous mutant newborns die at birth with atelectatic lungs which have the morphological characteristics observed in 16-18 day fetuses. An initial goal of the proposed research is the characterization of any pleiotropic effects of the mutation. The major long-term goal is determination of the precise morphological, biochemical, and developmental effects of the mutation on the lungs of nku homozygotes and in the small proportion of symptomatic heterozygotes. The lungs of homozygous mutant and control newborns will be studied intensively at the light microscope level, and a variety of selective histochemical methods will be utilized. The ultra-structural characteristics of affected mutant lungs will be analyzed at the electron microscope level, and a major focus will involve determining which of the diverse kinds of cells found in normal lungs are affected by the mutation. Since the final functional differentiation of the mammalian lung is correlated with deposition of specific phospholipids ("surfactant") on alveolar surfaces, the lipid composition of the lungs of homozygous mutant newborns or late fetuses and controls will be qualitatively and quantitatively compared by chromatographic methods. Direct and indirect physical measurements of the surface tension of mutant lung extracts will also be made. A major thrust of the proposed research will be an investigation of the effects of the nku mutation on the prenatal differentiation of the lung. In a retrograde study, litters of various gestational ages will be analyzed morphologically and biochemically in an effort to characterize the temporally or structurally aberrant developmental pattern in the lungs of mutant fetuses. A variety of experiments testing lung function in heterozygous carriers will provide information on the physiological effects of the nku mutation. In addition the effects environmental factors, such as physical stress of hypoxia, which may influence the expressivity of the nku mutation in heterozygotes will be studied.